Matching Treatment Choice to the Pathophysiology of Sleep - PowerPoint Presentation

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Matching Treatment Choice to the Pathophysiology of Sleep

Supported by an educational grant from Jazz Pharmaceuticals, Inc.

EPISODE 2

Richard K. Bogan, MD, FCCP, FAASM

President of Bogan Sleep Consultants, LLC

Medical Officer, SleepMed, Inc.Director, SleepMed of South CarolinaAssociate Clinical Professor, University of South Carolina School of Medicine, Colombia, SCAssociate Clinical Professor, Medical University of South Carolina

Charleston, SC

Yves Dauvilliers, MD, PhD

Professor of Neurology and PhysiologyUniversity of Montpellier

Director, Sleep-Wake Disorders CentreDepartment of NeurologyGui de Chauliac HospitalMontpellier, France

Learning Objective

Evaluate the significance of mechanism of action when selecting optimal treatment of EDS in patients with OSA or narcolepsy.

Normal Regulations of Sleep and Wake Systems

ORX = orexin

Saper CB, et al. Nature. 2005;437(7063):1257-1263.

Arousal System

Sleep

Onset

System

Hypothalamus

Pons

Medulla

Brainstem

Brainstem

Hypothalamus

Pons

Medulla

Sleep

Off

On

Awake

Neurotransmitters Involved in the Sleep-Wake Cycle

Acetylcholine

Histamine

Dopamine

Serotonin

Orexin

Norepinephrine

Neurobiology of NT1:

Loss

of

Orexin

/

Hypocretin

Neurons

CSF =

cerebrospinal

fluid

; EDS = excessive daytime sleepiness; SOREMP =

sleep onset REM periods

Sakuri T, et al. Orexin (hypocretin) and narcolepsy. In: The Genetic Basis of Sleep and Sleep Disorders. 2013.

Narcoleptics

Controls

Destruction of

hypocretin

(

Hcrt

) neurons

Absence of CSF

hypocretin

Cataplexy

EDS

SOREMP

NARCOLEPSY TYPE 1 (NT1)

Neurobiology of NT2:

Pathology of Lateral Hypothalamus?

GABA = gamma-aminobutyric acid;

MCH = melanin concentrating hormone;

REM = rapid eye movement

Peyron

C, et al.

Sleep Med

. 2011;12(8):768-772.

Narcolepsy

Cataplexy

Idiopathic

Hypersomnia

Post-traumatic

HypersomniaNeurologicalControls

CSF MCH level (

pg/ml)

Sleep-wake instability

with high REM sleep propensity

Partial lesion of Hcrt neurons? Increased activity of MCH neurons?

Circadian disturbances to explain the high REM sleep propensity

No association

between

MCH, histamine, and hypocretin

levels, EDS, SOREMPs,

cataplexy

NT2: Problem with phenotyping and stability of NT2. Unclear pathophysiology? No identified specific biomarker.

GABA

Sleep

Hypocretin

HA

/ NA / 5HT

Wake

Is

there

biological

dysfunction

?

Neurobiology of EDS in OSA

Problem with phenotyping

Assessment of EDS: Interviews, questionnaires (e.g., Epworth Sleepiness Scale)Objective data: MSLT, MWT, Osler…First exclusion Residual AHI, bad

compliance

with

CPAP,

leaks

…

Comorbid

depression

,

obesity, drug

intakeInsufficient sleep syndromeCentral hypersomnolence disordersNeed to define homogeneous criteria for this condition between sleep centersNo identified pathophysiology: Really unique?AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; MSLT = Multiple Sleep Latency Test; MWT = Maintenance of Wakefulness Test; OSA = obstructive sleep apneaGarbarino S, et al.

Front Neurol. 2018;9:505.

Determining a Target for Therapeutic Intervention

Based

on:

Symptom

(EDS)

severity

?

Background

disorder

(

narcolepsy

, OSA…)?

SXB

= sodium oxybate; GHB = gamma-hydroxybutyrateSzabo ST, et al. Sleep Med Rev. 2019;43:23-36.Spinal motor neurons

Locus coeruleusDorsal raphe nucleusVentral tegmentaHypothalamuCortexSSRI

SNRI/TCA

Stimulants/Solriamfetol

GHB/SXB/JZP-258

Pitolisant

Mechanisms of Action of Current and Novel Therapies for EDS

Affinities and Selectivity

Traditional stimulants

(e.g., methylphenidate, dextroamphetamine)

High affinity, non-selective for the DAT, NET, and SERT

1

Wake-promoting agents

(e.g., modafinil)

Low affinity, DAT selective

2

Solriamfetol

Low affinity,

DAT and NET selective

3

Sodium oxybate

High affinity,

GABA

B

selective

4

JZP-258

High affinity,

GABA

B

selective

5

DAT = dopamine transporter; NET = noradrenaline transporter; SERT = serotonin transporter; GABA = gamma-aminobutyric acid

1.

Rothman

RB, et al.

Synapse

.

2001;39(1):32-41.; 2.

Wisor

J.

Front

Neurol

.

2013;4:139.; 3. Markham A.

Drugs.

2019;79:785-790.;

4. Jazz Pharmaceuticals.

Product Monograph Including Patient Medication Information:

Xyrem

(Sodium

Oxybate

Oral Solution).

2018.

http://pp.jazzpharma.com/pi/xyrem.ca.PM-en.pdf.; 5. Drugs@FDA.gov.

Malhotra A, et al.

Sleep. 2019;43(2):zsz220.; Thorpy MJ, et al. Ann Neurol. 2019;85(3):359-370.;

Sukhal S, et al. J Clin Sleep Med. 2015;11(10):1179-1186.; Avellar A, et al. Sleep Med Rev. 2016;30:97-107.

Mechanism

of Action and

Clinical

Impact on EDS: Dopamine,

Norepinephrine

,

Serotonin

Monoaminergic neurons:

generally high rates of firing during wake (especially active wake), slow firing during non-rapid eye movement (NREM) sleep, and a virtual cessation of firing during REM sleep

High dopamine (DA) tone promotes wakefulness, while low DA tone promotes sleep.

Norepinephrine (NE) is key in arousal and maintaining normal sleep states

Serotonin precursors and reuptake inhibitors promote wakefulness.

Mechanisms of Action of Current and Novel Therapies for EDS

Affinities and Selectivity

Traditional stimulants

(e.g., methylphenidate, dextroamphetamine)

High affinity, non-selective for the DAT, NET, and SERT

1

Wake-promoting agents

(e.g., modafinil)

Low affinity, DAT selective

2

Solriamfetol

Low affinity,

DAT and NET selective

3

Sodium oxybate

High affinity,

GABA

B

selective

4

JZP-258

High affinity,

GABA

B

selective

5

DAT = dopamine transporter; NET = noradrenaline transporter; SERT = serotonin transporter; GABA = gamma-aminobutyric acid

1.

Rothman

RB, et al.

Synapse

.

2001;39(1):32-41.; 2.

Wisor

J.

Front

Neurol

.

2013;4:139.; 3. Markham A.

Drugs.

2019;79:785-790.;

4. Jazz Pharmaceuticals.

Product Monograph Including Patient Medication Information:

Xyrem

(Sodium

Oxybate

Oral Solution).

2018.

http://pp.jazzpharma.com/pi/xyrem.ca.PM-en.pdf.; 5. Drugs@FDA.gov.

Mechanism of Action and

Clinical Impact on EDS: Histamine

Histamine is a wake-promoting neurotransmitterHistamine neurons

promote arousal

Dauvilliers

Y, et al.

Sleep.

2019;42(11).pii:zsz174.

Partial cataplexy

REM sleep latency

EDS

Mechanism of Action and Clinical Impact on EDS

: GABA-B

Gowda CR, et al. CNS Spectrums. 2014;19:28–34.

GABA shuts off wake-promoting impact during the sleep-wake cycle

GABA-B selectivity results in OSA and narcolepsy:

Cataplexy

Slow-wave sleep

EDS

SXB, JZP-258

Identify key neurotransmitters involved in the sleep-wake cycle, particularly those involved in narcolepsy (type 1 and type 2) and OSA

Recognize how therapies targeted to the key neurotransmitters in the sleep-wake cycle exert their therapeutic effect on EDS in narcolepsy and OSA

SMART Goals

S

pecific,

M

easurable,

A

ttainable,

R

elevant,

T

imely

Additional Abbreviations

5-HT = 5-hyroxytryptamine

AC = anterior commissureAch = acetylcholineBF = basal forebrainCa = calciumcAMP = cyclic adenosine monophosphate

DAG = diglyceride

GHB = gamma-hydroxybutyrate

GLU = glutamine

H = hydrogen

HA = hyaluronic acid

HDC = histidine decarboxylase

HNMT = histamine N-methyltransferase

ir

= iridium

K = potassium

LDT = laterodorsal tegmental hormoneLH = lateral hypothalamusMAO = monoamine oxidasesNA = nucleus accumbensNa = sodiumNMDAR = N-methyl-D-aspartate receptorORX = orexinPAG = periagueductal grayPIP2 = phosphatidylinositol diphosphatePKA = protein kinase APKC = protein kinase CPLC = phospholipase CPPT = pedunculopontine tegmental nucleusTMN = tuberomammillary nucleusVLPO = ventrolateral preoptic nucleusVMAT = vesicular monoamine transporter

To receive CME/CE credit, click on the link to complete the post-test and evaluation online. Be sure to fill in your

ABIM ID number and

DOB (MM/DD) on the evaluation, so we can submit your credit to ABIM.

http://www.cmeoutfitters.com/TST43735

Participants can print their certificate or statement of credit immediately.

How to Collect Credit for this Activity

Visit the

Sleep Disorders Hub

Free resources, education, and tools for both HCPs and patients about EDS.www.cmeoutfitters.com/sleep-disorders-hub/

“I Shouldn’t Be This Sleepy”: A Look Into EDS

EPISODE 1

EPISODE 3

www.CMEOutfitters.com

Differentiators When Choosing Novel Treatment Options for EDS

EPISODE 4

Diagnosis and Treatment of Pediatric Narcolepsy with Cataplexy